Halo-substituted phenoxymethyl oxazolidones



United States Patent The present invention relates to certainhalo-substituted phenoxymethyl oxazolidones and is more particularlyconcerned with such compounds which are useful as interneuronal blockingagents or depressants of central synaptic transmission.

The compounds of the present invention have the general formula: I

wherein R is hydrogen or ahydrocarbon radical containing up to andincluding eight carbon atoms and selected from lower-alkyl, cycloalkyl,containing five through seven carbon atoms in the ring, benzyl, andphenethyl, wherein R is selected from hydrogen and halogen, at least oneR being halogen. Preferably any lower-alkyl radical contains not morethan three carbon atoms and, while the halogen may be iodo, bromo,chloro, or fluoro, the latter three are most suitable and the preferredhalogen is chlorine. Compounds wherein the R attached to the threenitr'ogen of-the oxazolidone' ring is hydrogen are likewise preferred.

These compounds of the present invention, characterized by the presenceof one or more halogen substituents on the phenyl ring, which must be ineither or both of the three (meta) and four (para) positions have beenfound to have superior activity of the aforementioned type and to beable to block abnormal nervous impulses which give rise to spasm. Theyshow high activity in standard testing procedures. They are especiallyeffective against electroshock-induced convulsions, which activity isindicative of ultimate anticonvulsant, relaxant, tranquilizing andsimilar clinical use in human beings, e. g., against grand or petit malepilepsy.

The activity of the compounds of the invention is surprisingly superiorto that of the known, and previously most active, 2mono-substitutedphenoxymethyl oxazolidones of an otherwise similar structure, and iscorrelated with their structural specificity. The fact that they possesssuperior anticonvulsant activity of one specific type, in a far greatermeasure than anticonvulsant activity of other types, makes themparticular-1y useful in the instances where specificity of treatment,rather than general anticonvulsant therapy, is indicated or desirable,and makes possible a directed approach, using the compounds of theinvention, to specific interneuronal or synaptic target organs or areas.While the compounds do differ among themselves in the magnitude of theirrespective activities, they are generally characterized 'by the type andmeasure of activity indicated in the foregoing.

It is accordingly an object of the present invention to provide certainhalo-substituted phenoxyrnethyl oxazolidones having the foregoingstructure and utility, and processes for the production thereof. Otherobjects will become apparent hereinafter.

In the formulae herein, R may represent, for example, besides hydrogen,the following radicals: lower-alkyl radicals, of both straight andbranched-chain nature, such as methyl, ethyl, propyl, isopropyl,n-butyl, sec. butyl, amyl, hexyl, and the like; cycloalkyl such ascyclopentyl, cyclopentylethyl, cyclohexyl, cycloheptyl,ethylcyclopentyl,

methylcyclohexyl, cyclohexylmethyl, ethylcyclohexyl, and the like;benzyl and phenethyl; and the like.

The halo-substituted phenoxymethyi oxazolidones of the invention may heprepared in a number of ways. For example, the5-halophenoxymethyl-Z-oxazolidones wherein R in the foregoing formula ishydrogen (and which are therefore unsubstitued at the oxazolidone threenitrogen atom) may be prepared by reacting a selected3-halophenoxy-1,2-propanediol (having the predetermined substituents onthe phenyl ring) and urea, preferably in an approximately 1:2 molarratio, by heating at an elevated temperature, usually C. to 200 C. andpreferably at about C., with or without a solvent. A fusion process ispreferably employed. The time required for complete reaction is usuallyat least three hours and the technique of rapidly heating the reactionmixture to the desired reaction temperature is advantageously followed.On completion of the reaction, the crude oxazolidone may be dissolved ina suitable solvent and recovered therefrom for purification purposes byusual procedure. Alternatively, a selected3-halophenoxy-l-chloro-Z-propanol may be reacted with urea instead ofthe 3-halophenoxy- 1,2-propanediol, using the same molar ratios andunder the same reaction conditions.

Moreover, when R is hydrogen, the S-halophenoxymethyl-Z-axazolidones mayalso be prepared by reacting a selected3-halophenoxy-2.-hydroxy-l-propyl-carbarnate and urea, preferably inapproximately equimolar quantities, at elevated temperatures,advantageously by heating the reactants together in the temperaturerange of 170 to 200 C., usually for periods as long as five hours forcompletion of the reaction, and separating the crude oxazolidone. Thepure oxazolidone may be obtained by fractional distillation or bycrystallation from an oxygenated solvent. The carbamate startingmaterial may in turn be prepared according to known procedure byreacting the selected 3-hal0phenoxy-l,Z-propanediol with an equimolarquantity of phosgene in the cold in the presence of an organic aminebase, such as pyridine or dimethyl aniline, to produce an intermediatechlorocarbonate compound, which is then reacted with ammonium hydroxideto yield the desired starting carbamate.

The substituted5-hal-ophenoxymethyl-3hydrocarbonsubstituted-Z-oxazolidones (wherein Rin the formula is a hydrocarbon radical), are conveniently prepared byaminating the selected 3-halophenoxy-l-chloro-Z-propanol employing aselected primary amine, such as methylamine, ethylamine, isopropylamine,butylamine, hexylamine, cyclohexylamine, benzylamine, phenethylamine, orthe like, according to known procedure, to yield a starting substituted3-halophenoxy-l-amino-Z-propanol having a nitrogen substituentcorresponding to that desired in the final S-halo-phenoxymethyl 3 Nsubstituted-Z-oxazolidone. The desired product is prepared by reactingtogether approximately equimolar quantities of the intermediateN-substituted amino alcohol and a ring closure agent, which may be adialkyl carbonate, at an elevated temperature, ordinarily about 95100 C.or thereabout for fifteen minutes to several hours, in the presence of abasic catalyst, such as sodium, potassium, their hy droxides, alkoxides,hydrides, and amides, e.g., sodium ethoxide, potassium hydride, sodiumamide, or the like, and preferably in a hydrocarbon solvent. Dialkylcarbonates, particularly di-lower alkyl carbonates, suCh as di-methylcarbonate, diethyl carbonate, di-n-propyl carbonate, di-n-butylcarbonate, di-sec.-butyl carbonate, .and the like, are suitable ringclosure agents. Carbonyl chloride may be substituted for the dialkylcarbonate; in such case, a lower temperature, usually below about 35 C.,is employed. Starting substituted 3-halophenoxy-l-chloro-3-propanols arein turn prepared in conventional manner by condensing the selectedsubstituted phenol with epichlorohydrin. The final substituted 5-halophenoxymethyl-3-N substituted-2-oxazolidones may be distilled fromthe reaction mixture after removal of the hydrocarbon solvent-alcoholazeotrope which forms during the reaction, and recrystallized, orrecovered and worked up in other conventional manner.

The following examples are given by way of illustration only, and arenot to be construed as limiting.

Example 1.5-(p-chlorophenoxymethyl) -2-0xaz0lid0ne A mixture of 40.5grams (0.20 mole) of 3-p-chlorophenoxy-l,2-propanediol and 24.0 grams(0.40 mole) of urea was heated at 195-200 C. for five hours and pouredinto water. The oil was extracted with ethyl acetate, which was driedover sodium sulfate, filtered and concentrated. A crude yield of 25.9grams (57%) of solid material was obtained, which after severalcrystallizations from ethyl acetate melted at 143.5-146 C.; M.W. 227.65.

Analysis.Calculated for C I-I ClNO N, 6.15.

Found: N, 6.14.

This compound was far superior to the corresponding o-chloro compound instandard anticonvulsant tests, and was at least five times as potent inthe standard rotarod test.

Example 2 .-5 p-bromophenoxymethyl 3 -ethyl-2- oxazolidone To a solutionof 44.0 grams (0.16 mole) of 3-p-bromophenoxy-l-ethylamino-2-propanoland 19.0 grams (0.16 mole) of diethyl carbonate in 200 ml. of iso-octanewas added 0.1 gram of sodium metal. The mixture was stirred and heatedat 95-100 C. for 30 minutes, while the ethanol/iso-octane azeotrope wasallowed to distill out. The reaction was practically complete in 15minutes and the insoluble oxaz-olidone precipitated from solution.Yield, 48.4 grams (98.2%); melting point, 122.5 C. Recrystallizationfrom iso-octane did not elevate the melting point. M.W. 300.16.

Analysis.-Calculated for C H BrNO C, 48.02;'H, 4.70; N, 4.67. Found: C,48.19; H, 4.89; N, 4.44.

Exam pl 3 m-clzloropllenoxymetlzyl -2-0xaz0lia'0ne A mixture of 40.5grams (0.20 mole) of 3-m-chlorophen0xy-1,2-propanediol and 24.0 grams(0.40 mole) of urea was heated at 195-200 C. for five hours and pouredinto water. The oil was extracted with ethyl acetate, dried over sodiumsulfate, filtered and concentrated. A crude yield of about 26 grams(57%) of solid material was obtained, which after severalcrystallizations from ethyl acetate melted at 965-97 C.; M.W. 227.65.

Analysis.-Calculated for C H ClNO N, 6.15. Found: N, 6.14.

Example 4.5-(p-br0m0phenoxymethyl)-2-0xaz0lid0ne A mixture of 0.20 moleof 3-p-bromophenoxy-1,2-

4 5-(p-chlorophenoxymethyl)-3ethyl-2-oxazolidone precipitates fromsolution. Yield about 98%; M.W. 116-117" C. Recrystallization fromiso-octane does not elevate the melting point. M.W. 255.71. Besides highactivity in the loss of righting reflex and anti-electroshock tests,this compound showed high activity against metrazol-induced spasm.

Example 6 .5 m-chlorophenoxymethyl -3 -pr0py l-2- oxazolidone To asolution of 0.07 mole of 1-propylamino-3-(mchlorophenoxy)-2-propanol and8.3 grams (0.07 mole) of ethyl carbonate in 200 ml. of iso-octane isadded 0.1 gram of sodium metal. The mixture is stirred and heated at95-100 C. for tw-o hours while the ethanol-iso-octane azeotrope isallowed to distill out. At the end of the first hour, an additional 0.1gram of sodium is added. Upon cooling, an oily layer separates and theiso-octane is decanted therefrom. The residue is recrystallized from dryisopropyl ether. The yield is about The product is subjected toelemental analysis; carbon, hydrogen, and nitrogen content confirm thestructure of the desired product.

Example 7.5-(p-chlorophenoxymethyl) il-hydrocarbon-Z-oxazolidones In themanner of the preceding Examples 2, 5, and 6, other 3-N-substitutedoxazolidones are produced by starting with the appropriate l-substitutedamino-3-(halophenoxy)-2-propanol, which is in turn prepared by reactingthe selected primary amine with the3-(halop'henoxy)-1-chloro-2-propanol. In this manner, starting with'l-propylamino, l-hexylamino, l-cyclopentylamino,

. chlorophenoxymethyl)-3-methylbenzyl-2-oxazolidone,

, chlorophenoxy)-2-propan0l.

propanediol and 24.0 grams (0.40 mole) of urea was heated at 195-200 C.for five hours and poured into water. The oil was extracted with ethylacetate, dried over sodium sulfate, filtered and concentrated. A crudeyield of 20 grams of solid S-(p-bromophenoxymethyl)-2- oxazolidone wasobtained, which after several crystallizations from ethyl acetate meltedat 153-154 C.; M.W. 272.11.

Example 5.-5-(p-chlorophenoxymethyl)-3-ethyl-2- oxazolidone Example8.5-(m-fluoro and p-fluorophenoxymethyl)-2-oxaz0lid0nes In the manner ofExamples 1, 3, and 4, the compoundsS-(m-fluorophenoxymethyl)-2-oxazolidone and5-(p-fiuorophenoxymethyl)-2=oxazolidone are prepared by reacting3-(m-fluorophenoxy)-1,2-propanediol and3-(p-fiu0rophenoxy)-1,2-propanediol (or the corresponding l-chloro-2-propan0ls or 2-hydroxy-l-propyl-carbamates) with urea and separating,working up the product, and purifying it in the usual manner.

Example 9.-5 (3,4-dichlorophenoxymethyl)-2-0xaz0lidone and 5 (3, 4-dibromophenoxymethyl)-2-oxaz0lidone In the manner of Examples 1, 3, and4, the compounds 5-(3,4-dichlorophenoxymethyl)-2-oxazolidone and 5-(3,4-dibromophenoxymethyl)-2-oxazoliclone are prepared by reacting3-(3,4-dichlorophenoxy) 1,2-pr0panediol or 3-(3,4-dibromophenoxy)-l,2-propanediol (or the corresponding1-chloro-2-propanols or 2-hydroxy-1-propylcarbamates) with urea andseparating, working up the product, and purifying it in the usualmanner.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described asobvious modifications and equivalents will be apparent to one skilled inthe art, and

5 6 the invention is therefore to be limited only by the scope Beasleyet :aL, Chem. Abstracts, v01. 51, col, 8723 of the appended claims.(1957).

I claim: Blajot et al., 743 0G. 933, June 23, 1959. 1.S-(p-chlorophenoxymethyl)2-oxazolidone. Fieser et 211., OrganicChemistry (Reinhold), pp. 2. 5-(m-chlorophenoxymethyl)-2-0xaz0lidone. 5624-626 (1956).

Karrer, Organic Chemistry (Elsevier), pp. 434, 445 References Cited bythe Examiner Noller, Chem. of Org. Compounds, 2nd ed. (Saund- UNITEDSTATES PATENTS pp 4 404 (1957).

2,895,960 7/1959 Lunsford 260-3073 OTHER REFERENCES ALEX MAZEL, PrimaryExan'ziner.

Am. Cyanamid, Australian Abstract, 42986/58, May 7, IRVING MARCUS LIDOFFExammm- 1959. D. T. MCCUTCHEN, Assistant Examiner.

1. 5-(P-CHLOROPHENOXYMETHYL)2-OXAZOLIDONE. 2.5-(M-CHLOROPHENOXYMETHYL)-2-OXAZOLIDONE.